4-((1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile i.e. Crisaborole, of formula (I),

is a non-steroidal topical inhibitor of phosphodiesterase 4 (PDE4), in particular of phosphodiesterase 4B (PDE4B), an enzyme that regulates the inflammation by degradation of adenosine monophosphate (cAMP). PDE4 is hyperactivated in atopic dermatitis and leads to an increase of the symptoms of said disease. Inhibition of PDE4 blocks the release of pro-inflammatory cytokines and in clinical studies Crisaborole showed a significant improvement in pruritus and other symptoms of the disease.
On Dec. 14, 2016, the FDA approved Crisaborole as ointment for topical treatment of atopic dermatitis in adults and children aged two years and more.
Crisaborole is known from U.S. Pat. No. 8,039,451, which claims the compound as such and pharmaceutically acceptable salts thereof. One synthesis of Crisaborole is described in Bioorg. Med. Chem. Lett., 2009, 19, 2129-2132, but the therein disclosed process is rather long and complex (Scheme 1).

The synthesis comprises the protection of the commercially available aldehyde 1 with ethylene glycol in presence of p-toluenesulfonic acid in toluene to give intermediate 2. The subsequent reaction with commercially available 4-fluorobenzonitrile in DMF provides the acetal 3, which is then deprotected to give aldehyde 4. Intermediate 4 is treated with NaBH4 in methanol to give the benzyl alcohol 5 that is then protected as tetrahydropyranyl (THP) to give compound 6. Crisaborole 7 is finally obtained after lithiation, reaction with an alkylborate and acidic hydrolysis. The yields of these final steps from intermediate 6 are just 37 to 44%. The formation of the boronic acid to give Crisaborole can also be performed starting from the unprotected intermediate 5, but the yields in this case are even lower.
Three crystalline forms of Crisaborole of formula (I) have been disclosed in patent application WO2017/093857 filed by Anacor Pharmaceuticals Inc. on 23 Nov. 2016. A crystalline form, named crystalline Form 1, has been specifically claimed with a XRPD spectrum, wherein the characteristic peaks are found at about 6.0, 12.1, 14.1, and 15.4±0.2° in 2θ, using CuKα (λ=1.54 Å) radiation. According to WO2017/093857, the crystalline Form 1 “was identified as the commercial form and was utilized in Phase 3 studies”. The crystalline Form 2 has been used in clinical trials of phase 1 and 2, and according to the inventors the crystalline Form 3 is typically found after rapid evaporation of the solvents, such as ethyl acetate, methyl ethyl ketone or methyl-tert-butyl ether.
WO2017/093857 provides procedures for the preparation of all three crystalline forms of Criaborole of formula (I), but the methods disclosed in the examples for the crystalline Forms 1 and 3 make use of previously obtained seed crystals of Form 1 and Form 3. However, the application is silent about the preparation of said seeds. The authors of the present invention have repeated exactly the procedures reported in WO2017/093857 for the preparation of Form 1 without using any seed crystal and obtained Crisaborole in crystalline Form 2.
Therefore, there remains a need of a simpler and more advantageous alternative method for preparing Crisaborole of formula (I). This new method should in particular consist of fewer synthetic steps, should avoid an extensive use of protecting groups and improve the overall atom economy of the process. Said process should also be cost effective, safe for human and environment, and should use mild reaction conditions in order to obtain Crisaborole of formula (I) in high yields.
In addition, there remains also a need for a procedure for preparing Crisaborole in crystalline Form 1 sufficiently described to be repeated by a person skilled in the art. In addition, there is the need for an environmentally friendly process, which is industrially safe and/or simple, which allows to obtain the desired polymorph in a particularly advantageous manner, in high yields and purity, and which is feasible on an industrial scale.